Opinion
MDL Docket No. 1203.
June 29, 2000
MEMORANDUM AND PRETRIAL ORDER NO.
Presently before the court are the Phentermine Defendants' and American Home Products Corporation's ("AHP") (collectively, "Defendants") motions to exclude the expert testimony of plaintiffs' experts Paul Wellman, Ph.D. and Timothy Maher, Ph.D. pursuant to Federal Rules of Evidence 702 and 703, Plaintiffs' Motion to Update Daubert Record and the responses thereto. For the reasons set forth below, the court will grant in part and deny in part the motions to exclude expert testimony and will deny the motion to update the record.
Eon Labs Manufacturing, Inc.; Fisons Corporation; Gate Pharmaceuticals, a division of Teva Pharmaceuticals USA, Inc.; Geneva Pharmaceuticals, Inc.; Ion Laboratories, Inc.; Jones Medical Industries, as successor to Abana Pharmaceuticals, Inc.; Medeva Pharmaceuticals, Inc.; MCR/American Pharmaceuticals, Inc.; Qualitest Pharmaceuticals, Inc.; Rosemont Pharmaceutical Corporation; Rugby Laboratories, Inc.; Shire Richwood, f/k/a Richwood Pharmaceutical Company, Inc.; SmithKline Beecham Corporation; United Research Laboratories, Inc.; and Zenith Goldline Pharmaceuticals, Inc.
I. BACKGROUND
Timothy Maher, Ph.D., a pharmacologist, and Paul Wellman, Ph.D., a behavioral psychologist, have been offered by various plaintiffs in this MDL No. 1203 to provide expert testimony concerning the alleged medical effects of phentermine in humans. Essentially, Plaintiffs seek to have Drs. Maher and Wellman offer the following opinions:
1. The fenfluramines (fenfluramine and dexfenfluramine) cause primary pulmonary hypertension ("PPH").
For a discussion of the Daubert issues concerning this opinion, see infra III.D.
1.1 Risk increases with duration.
2. The fenfluramines cause valvular heart disease ("VHD").
For a discussion of the Daubert issues concerning this opinion, see infra III.D.
2.1 Risk increases with dose.
2.2 Risk increases with duration.
3. Pondimin (fenfluramine) monotherapy had minimal clinical usage.
3.1 Levofenfluramine caused unpleasant side effects.
For a discussion of the Daubert issues concerning this opinion, see infra III.C, at footnote 23.
Levofenfluramine is the left molecule of fenfluramine.
3.2 Clinical efficacy required higher doses.
4. The clinical combination of Fen-Phen (fenfluramine and phentermine) intentionally exploited two pharmacological properties of phentermine.
4.1 Phentermine boosts the efficacy of dexfenfluramine.
4.2 Phentermine blunts the unpleasant side effects of levofenfluramine in Pondimin.
5. The pharmacology of phentermine caused a dramatic increase in the use of Pondimin in the United States and thus the vast majority of Pondimin-induced VHD and PPH.
6. The Fen-Phen combination induces greater cardiovascular toxicity than does fenfluramine alone.
6.1 Serotonergic mechanisms are implicated in the pathogenesis of both PPH and VHD.
6.2 Phentermine acts on serotonergic mechanisms in at least three ways:
• by inhibiting the enzyme monoamine oxidase ("MAO") which metabolizes serotonin;
For a discussion of the Daubert issues concerning this opinion, see infra III.C.1.
Dexfenfluramine is the right molecule of fenfluramine.
For a discussion of the Daubert issues concerning this opinion, see infra III.C.2.
For a discussion of the Daubert issues concerning this opinion, see infra III.B.
• by causing the release of serotonin; and
• by affecting serotonin receptors on heart valve tissue leading to cellular proliferation.
(Pls.' Post-Hr'g Mem. in Resp. to Defs.' Mots. to Exclude Expert Test. of Paul J. Wellman, Ph.D. and Timothy J. Maher, Ph.D. at 1-2.) Both the Phentermine Defendants and AHP filed motions to exclude the testimony of Drs. Maher and Wellman. Responses were filed and on March 7-8, 2000, the court held a Daubert hearing. At the hearing the following witnesses testified: (1) for Plaintiffs, Drs. Maher and Wellman; and (2) for the Phentermine Defendants, Anthony N. DeMaria, M.D., a cardiologist; Michael D. Gershon, M.D., a cellular biologist; Harihara M. Mehendale, Ph.D., a toxicologist; Charles V. Vorhees, Ph.D., a neurotoxicologist and neuropharmacologist; Timothy W. Higenbottam, M.D., a PPH expert; Mark T. Nelson, Ph.D., a pharmacologist; and Michael D. Decker, M.D., M.P.H., a specialist in epidemiology. Following the hearing, the parties filed posthearing submissions.
II. LEGAL STANDARD
Federal Rule of Evidence 702 imposes an obligation on a trial judge to "`ensure that any and all scientific testimony or evidence admitted is not only relevant, but reliable.'" Kumho Tire Co., Ltd. v. Carmichael, 526 U.S. 137, 147 (1999) (quoting Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579, 589 (1993)). The party offering the expert has the burden of proving admissibility under Rule 702. See Daubert, 509 U.S. at 592 n. 10 (citing Fed.R.Evid. 104(a)). In Daubert, the Court required that the subject of an expert's testimony must constitute "scientific knowledge." Id. at 589-90. "The adjective `scientific' implies a grounding in the methods and procedures of science," and "the word `knowledge' connotes more than subjective belief or unsupported speculation." Id. at 590. In addition, Rule 702 requires that expert evidence or testimony assist the trier of fact. See id. at 591. In other words, expert testimony must "fit" the issues in a case by having a "valid scientific connection to the pertinent inquiry" before the trier of fact. Id. at 591-92.
The Rule provides: "[i]f scientific, technical, or other specialized knowledge will assist the trier of fact to understand the evidence or to determine a fact in issue, a witness qualified as an expert by knowledge, skill, experience, training, or education, may testify thereto in the form of an opinion or otherwise." Fed.R.Evid. 702.
Faced with a proffer of expert testimony, the court must determine "whether the expert is proposing to testify to (1) scientific knowledge that (2) will assist the trier of fact."Id. at 592. In undertaking this gatekeeping function, the court must assess "whether the reasoning or methodology underlying the testimony is scientifically valid" and whether "that reasoning or methodology properly can be applied to the facts in issue." Id. at 592-93. In Daubert, the Court identified several factors to assist courts in evaluating whether a scientific theory or methodology constitutes reliable scientific knowledge. These include: whether the theory or technique can be or has been tested; whether the theory has been subjected to peer review and publication; whether a technique has a known or potential rate of error and whether there are standards controlling the technique's operation; and whether the theory or method has general acceptance in the scientific community. See id. at 593-94 (listing factors which may bear on inquiry, but stating that such factors did not establish definitive checklist or test). The court's role as a gatekeeper is a flexible one and these factors "are simply useful signposts, not dispositive hurdles that a party must overcome in order to have expert testimony admitted." Heller v. Shaw Indus., Inc., 167 F.3d 146, 152 (3d Cir. 1999).
The Third Circuit has listed other factors to consider as well. Together, these factors are:
(1) whether a method consists of a testable hypothesis;
(2) whether the method has been subject to peer review;
(3) the known or potential rate of error; (4) the existence and maintenance of standards controlling the technique's operation; (5) whether the method is generally accepted; (6) the relationship of the technique to methods which have been established to be reliable; (7) the qualifications of the expert witness testifying based on the methodology; and (8) the non-judicial uses to which the method has been put.In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 742 n. 8 (3d Cir. 1994).
Under Daubert and its progeny, the court must examine an expert's methodology and conclusions in order to ensure reliability. See Heller, 167 F.3d at 153 (stating that "a district court must examine the expert's conclusions in order to determine whether they could reliably follow from the facts known to the expert and the methodology used"). In General Electric Company v. Joiner, the Supreme Court instructed that:
conclusions and methodology are not entirely distinct from one another. Trained experts commonly extrapolate from existing data. But nothing in either Daubert or the Federal Rules of Evidence requires a district court to admit opinion evidence which is connected to existing data only by the ipse dixit of the expert. A court may conclude that there is simply too great an analytical gap between the data and the opinion proffered. General Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997).
In addition, a court should "exclude proffered expert testimony if the subject of the testimony lies outside the witness's area of expertise." 4 Weinstein's Fed. Evid. § 702.06[1], at 702-52 (2000); see Wehling v. Sandoz Pharms. Corp., 162 F.3d 1158 (4th Cir. 1998) (available at No. 97-2212, 1998 WL 546097, at *4 (4th Cir. Aug. 20, 1998)) (stating that pharmacist/toxicologist was unqualified to testify as to adequacy of drug warning where he had "never been involved with the drafting, regulation, or approval of product labeling for any prescription medication" and that "experience as a pharmacist, reading prescription labels and dispensing drugs, [did] not qualify him to testify about the adequacy of drug warnings"); Robertson v. Norton Co., 148 F.3d 905, 907 (8th Cir. 1998) (stating that, although ceramics expert "was undoubtedly qualified to testify about a manufacturing defect in an exploding ceramic grinding wheel, that did not qualify him as an expert on grinding wheel warnings," because, among other things, "[h]e had never designed a warning for a ceramic product" and "[h]is knowledge of ceramics would not provide the expertise on questions of display, syntax, and emphasis that the jury would expect from a bona fide warning expert"); Kent v. Howell Elec. Motors, No.Civ.A. 96-7221, 1999 WL 517106, at *5 (E.D. Pa. July 20, 1999) (excluding engineering expert from offering opinion as to adequacy of warnings because expert admitted he was not expert in warning design); Tyler v. Sterling Drug Co., 19 F. Supp. 2d 1239, 1245 (N.D. Okla. 1998) (excluding testimony of human factors psychologist as to product warnings); Estate of Lam v. Upjohn Co., No.Civ.A. 94-003-H, 1995 WL 478844, at *2 (W.D. Va. April 21, 1995) (recommending exclusion of expert testimony on pharmaceutical warnings when expert had "no academic training or regulatory experience and ha[d] never participated in any FDArelated proceedings addressing what constitutes an adequate warning"). In other words, a party cannot qualify an expert generally by showing that the expert has specialized knowledge or training which would qualify him or her to opine on some other issue. See Redman v. John D. Brush and Co., 111 F.3d 1174, 1179 (4th Cir. 1997) (holding that metallurgic expert could testify about properties and characteristics of metal safe, but was not qualified to testify about industry standards for design of safes because "he had never before analyzed a safe, engaged in the manufacture or design of safes, or received any training regarding safes," and, "[e]ven more importantly, he was not personally familiar with the standards . . . used in the safe industry"); Barrett v. Atlantic Richfield Co., 95 F.3d 375, 382 (5th Cir. 1996) (holding that ecologist with expertise in behavior patterns of rats was not qualified to opine on source of chromosomal damage exhibited by rats, nor was he qualified to opine on whether humans faced increased health risks from exposure to chemicals).
Furthermore, an expert's opinion must be based on scientific, technical or other specialized knowledge and not on "subjective belief or unsupported speculation." Daubert, 509 U.S. at 590; see Textron, Inc. v. Barber-Colman Co., 903 F. Supp. 1558, 1564 (W.D.N.C. 1995) (stating that "not every opinion offered by an expert is an expert opinion . . . [and that] an expert's opinion must be an `expert' opinion (that is an opinion formed by the witness' expertise) rather than simply an opinion broached by a purported expert"). Moreover, testimony of an expert that constitutes mere personal belief as to the weight of the evidence invades the province of the jury. See McGowan v. Cooper Indus., Inc., 863 F.2d 1266, 1273 (6th Cir. 1987) (holding that although expert's testimony on industry custom was admissible, "once the jury heard all of the evidence on the scope of [the defendant's] duty, it was as qualified as [the expert] to determine whether [the defendant] breached that duty"); STX, Inc. v. Brine, Inc., 37 F. Supp. 2d 740, 768 (D. Md. 1999) (stating that "`an expert's opinion on the ultimate legal issue must be supported by something more than a conclusory statement'") (quoting In re Buchner, 929 F.2d 660, 661 (Fed. Cir. 1991)), aff'd, 211 F.3d 588 (Fed. Cir. 2000), aff'd, No. 99-1540, 2000 WL 564010 (Fed. Cir. May 8, 2000); Securities and Exch. Comm'n v. Lipson, 46 F. Supp. 2d 758, 763 (N.D. Ill. 1998) (holding that expert's training and experience as accountant did not "specially equip him to divine what [the defendant] truly believed" about reliability of financial reports and that any opinions offered in that regard were "at worst, speculation [and] at best, they are credibility choices that are within the province of the jury").
In undertaking a Daubert analysis, the court "should also be mindful of other applicable rules." Daubert, 509 U.S. at 595. Federal Rule of Evidence 703 "provides that expert opinions based on otherwise inadmissible hearsay are to be admitted only if the facts and data are `of a type reasonably relied upon by experts in the particular field in forming opinions or inferences upon the subject.'" Id. (quoting Fed.R.Evid. 703). Under Rule 703, "[i]f the underlying data are so lacking in probative force and reliability that no reasonable expert could base an opinion on them, an opinion which rests entirely upon them must be excluded." In re Paoli R.R. Yard PCB Litig., 35 F.3d at 748 (quoting In re "Agent Orange" Prod. Liab. Litig., 611 F. Supp. 1223, 1245 (E.D.N.Y. 1985)).
III. DISCUSSION
The court will grant in part and deny in part the Phentermine Defendants' and AHP's motions to exclude the expert testimony of Drs. Maher and Wellman. Initially, the court will address the qualifications of Drs. Maher and Wellman. Then, the court will address the opinions of Drs. Maher and Wellman, the basis for them, and the evidence introduced at the Daubert hearing. Last, the court will address Plaintiffs' motion to update the record.
A. Qualifications of Drs. Maher and Wellman
Dr. Maher is a pharmacologist. He is Professor of Pharmacology, the Sawyer Professor of Pharmaceutical Sciences and Dean of Research Sponsored Programs at the Massachusetts College of Pharmacy. Dr. Maher is also the Chief Executive Officer of Longwood Pharmaceutical Research, Inc. He is a lecturer in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology ("MIT"), a Visiting Scientist at the Clinical Research Center at MIT and a Visiting Instructor in the Department of Pharmacology at the University of New England College of Osteopathic Medicine. He has research experience involving monoamines and other neurotransmitters, and how drugs affect them in the both the brain and periphery. He has conducted research on the role of phentermine in the pathogenesis of heart valve disease and pulmonary hypertension, and has published those opinions. See Timothy J. Maher, et al., Phentermine and Other Monoamine Oxidase Inhibitors May Increase Plasma Serotonin When Given With Fenfluramines, 353 The Lancet 38 (1999) (Joint Ex. 2A at Tab 1 Ex. C); Valvulopathy or Primary Pulmonary Hypertension as Possible Consequences of Administering a Serotonin Uptake Blocker With a Monoamine Oxidase Inhibitor ("Phen-Fen"), 23 Cardiovascular Reviews Reports 312-13 (1999) (Joint Ex. 2A at Tab 1 Ex. D); P.J. Wellman and T.J. Maher,Synergistic Interactions Between Fenfluramine and Phentermine, 23 International Journal of Obesity 723-32 (1999) (Joint Ex. 2A at Tab 1 Ex. E); and Timothy J. Maher, et al., Does Phentermine Inhibit Monoamine Oxidase?, 353 The Lancet 1362-63 (1999) (Joint Ex. 2A at Tab 1 Ex. F). Dr. Maher is not a medical doctor, nor does he have expertise in epidemiology, pulmonology, cardiology, PPH, VHD or serotonin systems. He has never treated patients nor prescribed medications.
The term periphery refers to the area of the body excluding the brain and spinal cord.
Dr. Wellman is a behavioral psychologist. He is Professor and Head of Psychology at Texas A M University. Dr. Wellman is a member of several psychological societies and is an ad hoc reviewer for several scientific journals. (Joint Ex. 3A at Tab 2, ¶ 1.) He has studied anorectic drugs and their effects in animals and has extrapolated from the animal data to the probable effects those drugs may have on humans. Dr. Wellman co-authored with Dr. Maher the article entitled Synergistic Interactions Between Fenfluramine and Phentermine, 23 The International Journal of Obesity 723-32 (1999). (Joint Ex. 3A at Tab 1 Ex. C.) Dr. Wellman is not a medical doctor and has never treated patients nor prescribed medications. Dr. Wellman does not consider himself an expert in epidemiology, pulmonology, cardiology, PPH or VHD.
Primarily, his research has focused on how phenylpropanloamine ("PPA") reduces appetite in animals. (Tr. 3/7/00 at 168.)
The court notes an initial problem in the qualifications of both Drs. Maher and Wellman. Neither Dr. Maher nor Dr. Wellman are medical doctors who have treated patients, yet both proffer opinions regarding PPH and VHD causation in humans. The court recognizes that this does not per se preclude Drs. Maher or Wellman from testifying about causation of these diseases in humans. See Holbrook v. Lykes Bros. SS Co., Inc., 80 F.3d 777, 782 (3d Cir. 1996) (stating that "witness may be competent to testify as expert even though they may not, in the court's eyes, be the `best' qualified"); In re Paoli RR Yard PCB Litig., 916 F.2d 829, 856 (3d Cir. 1990) (holding that district court abused its discretion in excluding doctors "because the experts did not have the degree or training which the district court apparently thought would be most appropriate"). Nonetheless, Drs. Maher and Wellman do not have any general expertise regarding disease causation in humans. The court will take into consideration Dr. Maher's and Dr. Wellman's absence of expertise in human disease causation as it examines the reliability of their opinions and in determining "fit" under theDaubert standard. See Smith v. Rasmussen, 57 F. Supp. 2d 736, 766 (N.D. Iowa 1999) (stating that Supreme Court has "made clear that a person, although qualified as an expert in one area of expertise, may be precluded from offering opinions beyond that area of expertise, or that are founded on a reliable methodology").
B. Opinion That the Fen-Phen Combination Induces Greater Cardiovascular Toxicity Than Does Fenfluramine Alone.
Drs. Maher and Wellman opine that phentermine acts synergistically with fenfluramine to increase the risk of PPH and VHD. The "most plausible and likely mechanisms by which phentermine increases the toxicity of fenfluramine is by interfering with the clearance of serotonin from the lungs and the immediate local areas of pulmonary arteries and left side of the heart, through monoamine oxidase inhibition, and/or by increasing the local levels of extra-cellular serotonin by triggering the release of serotonin from platelets." (Pls.' Post-Hr'g Mem. in Resp. to Defs.' Mots. to Exclude Expert Test. of Paul J. Wellman, Ph.D. and Timothy J. Maher, Ph.D. at 21; Joint Ex. 2A (Maher) at Tab 3 ¶ 3(j).) Drs. Maher and Wellman both admit that their views on this subject are not generally accepted in the scientific community. The court recognizes that Dr. Maher's and Dr. Wellman's views have been published in a peer-reviewed journal. The court will consider these factors in undertaking its Daubert analysis.
A platelet is a cell fragment that floats freely in the blood plasma. (Joint Ex. 5 (Gershon) at Tab 2 ¶ 30.) Plasma is the fluid in which the cellular components of blood are suspended. Id. at 46 n. 16.
1. Epidemiological Data.
Scientists often rely upon epidemiologic studies to test hypotheses about disease causation in humans. A fundamental premise of epidemiology is the use of controls or comparison groups in scientific studies. (Joint Ex. 8, Stampfer Decl. ¶ 25.) Control groups are an essential component to epidemiological studies because many diseases occur in persons who have not been exposed to a particular drug or substance under study. Id. This is particularly significant here, where both PPH and VHD have a background rate. In other words, both PPH and VHD occur in persons who have not been exposed to phentermine alone or in combination with fenfluramine and/or dexfenfluramine.
The rate of disease in the unexposed population is called the "background rate." (Joint Ex. 8, Stampfer Decl. ¶ 25.)
Epidemiologists compare rates of disease in various populations to determine whether there is an increased risk of disease in those who used a particular substance in comparison to non-users. (Joint Ex. 8, Stampfer Decl. ¶ 26.) Thus, without utilizing a control group for comparison purposes, a conclusion that a substance caused a particular condition is scientifically unreliable. Id.
Plaintiffs concede that, at this time, no epidemiologic data support the position that phentermine, when combined with fenfluramine, increases the risk of PPH or VHD in humans. (Tr. 3/7/00 at 20.) In his testimony, Dr. Wellman also conceded this point. (Tr. 3/7/00 at 217.) Plaintiffs, however, argue that epidemiologic data are not necessary to demonstrate causation. (Tr. 3/7/00 at 25.)
2. Data Regarding Studies Performed on Whole, Live Animals.
Similarly, Plaintiffs have not shown any scientific evidence demonstrating that phentermine, when used in combination with fenfluramine, induces PPH or VHD in whole, live animals. (Tr. 3/7/00 at 225.) The biological mechanism of PPH is unknown and animal studies have not reproduced PPH in the laboratory. (Joint Ex. 9 (Higgenbottam) at Tab 5 ¶¶ 56, 59 63.) With respect to VHD, Dr. Wellman conceded that phentermine has never been shown to induce VHD in live, whole animals. (Tr. 3/7/00 at 225.)
Dr. Wellman has referred to the Bratter Study in suggesting that the combination of phentermine with fenfluramine has been shown to produce "what appears to be" VHD in animals. (Tr. 3/7/00 at 225; Supp. Mem. of Phen. Defs. in Support of Mot. to Exclude Expert Test. of Drs. Wellman and Maher Ex. 2.) This study cannot reliably support Dr. Wellman's conclusion. The Bratter study involved pregnant rats that were administered phentermine and dexfenfluramine. Although 25% of the offspring reported valvular thickening, none of the mothers were reported to have valvular thickening. No meaningful conclusion can be drawn from this finding. Offspring are connected to their mother's circulation through the placenta and there are a number of interactions dealing with circulation that could cause valvular thickening quite apart from the effects of the diet drugs on the heart. (Tr. 3/8/00 at 23.)
In addition, no rats in this study were administered phentermine or dexfenfluramine alone. Because the combination of phentermine and dexfenfluramine was not compared to dexfenfluramine alone, there is no way to determine whether valvular thickening was in any way caused by phentermine. Moreover, large doses of phentermine and dexfenfluramine were administered to the rats in the Bratter Study. (Supp. Mem. of Phen. Defs. in Support of Mot. to Exclude Expert Test. of Drs. Wellman and Maher Ex. 2 at R2.)
3. Serotonin Hypotheses.
The parties are divided as to whether serotonin is causally related to the pathogenesis of PPH and VHD. The Phentermine Defendants characterize serotonin as one of the many substances that is potentially responsible for PPH and VHD and which remains merely part of a hypothesis to be investigated further. See Joint Lit. Ex. 199 (Weir) at 2219 (stating that it is unlikely that serotonin is involved with PPH); Joint Lit. Ex. 169 (Rubin) at 195 (stating that "role of serotonin in the pathogenesis of PPH remains unclear"); Tr. 3/8/00 at 137 (Higgenbottam) (citing growing body of literature suggesting that serotonin is unlikely mechanism for PPH); Joint Ex. 4 (DeMaria) at Tab 2 ¶¶ 60-64 (stating that causal relationship between serotonin and VHD has not been established). Plaintiffs characterize serotonergic mechanisms as important to the pathogenesis of diet drug induced PPH and VHD. See Joint Lit. Ex. 56 (Egermayer) at 165 (stating that "serotonergic mechanisms are important in the pathogenesis of dietary pulmonary hypertension"); Joint Lit. Ex. 70 (Fristrom) (noting in study of drug Aminorex that there was relationship between serotonin and VHD and pulmonary hypertension); Joint Lit. Ex. 184 (Simonneau) (noting relationship between serotonin and VHD and PPH); Joint Lit. Ex. 65 (Fishman) (same).
The court will first examine whether there is any underlying data supporting Dr. Maher's and Dr. Wellman's opinions involving the connection between phentermine, when used in combination with fenfluramine, and PPH and VHD and serotonergic mechanisms. Dr. Maher's and Dr. Wellman's opinions are based upon various animal studies and human blood studies. Their opinions are grounded upon the notion that plasma serotonin levels are important in determining the cause of PPH and VHD and that phentermine produces elevated plasma serotonin levels. Both Drs. Maher and Wellman agreed that elevation of plasma serotonin was critical to their opinions. (Tr. 3/7/00 at 92-94, 227, 229-30 235-36.) Dr. Wellman testified that plasma serotonin is critical because it interacts with the tissues and organs of the body.
However, Plaintiffs have not set forth evidence demonstrating that phentermine, when used alone or in combination with fenfluramine, increases plasma serotonin in humans. (Tr. 3/8/00 at 11; Joint Ex. 5 (Gershon) at Tab 4 ¶¶ 48-50.) Drs. Maher and Wellman conceded that they could not identify any scientific evidence showing an increase in plasma serotonin levels in humans who ingested phentermine, alone or in combination with fenfluramine. (Tr. 3/7/00 at 96, 107-08 230.) Similarly, Drs. Maher and Wellman do not rely on any scientific evidence demonstrating that phentermine, either alone or in combination with fenfluramine, increases plasma serotonin levels in live animals. (Tr. 3/7/00 at 233-34; Tr. 3/8/00 at 11-12.) In fact, Dr. Wellman performed a rat study using phentermine alone that was inconclusive with regard to an increase of plasma serotonin levels. (Tr. 3/7/00 at 233-34.)
The Phentermine Defendants argue that a study by Dr. Redmon, et al. as well as another recent study support their position that plasma serotonin levels in patients who ingested phentermine and fenfluramine do not increase. (Joint Lit. Exs. 147 164.) Drs. Maher and Wellman dispute the Phentermine Defendants' interpretation of this data. More important, however, is that Drs. Maher and Wellman have not identified any scientific evidence to support their opinions that ingestion of phentermine, alone or in combination with fenfluramine, causes an increase in plasma serotonin levels in humans.
Lacking direct data to support their opinion that phentermine acts synergistically with fenfluramine to cause an increase in plasma serotonin, Dr. Maher's and Dr. Wellman's opinions are grounded primarily on theories involving serotonergic mechanisms. The court will examine these opinions regarding serotonergic mechanisms.
a. Monoamine Oxidase Inhibition
Monoamine oxidase ("MAO") is an enzyme that breaks down serotonin in the periphery. Drs. Maher and Wellman rely on in vitro animal studies and opine that phentermine inhibits MAO, resulting in increased serotonin in the periphery. There are several problems with both these studies and these opinions. Most importantly, the concentrations of phentermine used in the animal studies relied upon by Drs. Maher and Wellman are significantly higher than that ingested by humans. (Tr. 3/7/00 at 144 258-59.) Dr. Maher also opined that phentermine might accumulate at critical locales in the body, including the lung. (Tr. 3/7/00 at 95.) Dr. Maher relies on the Mehendale study for this proposition. (Joint Lit. Ex. 138.) However, Dr. Mehendale's experiment provides no basis for the claim that phentermine accumulates in human lung tissue. See infra III.B.3.b.
Dr. Maher acknowledges that the only human data on which he relies for his opinion that phentermine is an MAO inhibitor is his own study evaluating serotonin levels in the blood of human phentermine users. Dr. Maher's study did not find an increase in plasma serotonin levels. Instead, the study found an increase in platelet serotonin. Dr. Maher conceded that he is not aware of any scientific evidence showing that increased platelet serotonin leads to the development of PPH and VHD in humans. (Tr. 3/7/00 at 114.) In fact, the organs and tissues of the body are not exposed to serotonin in the platelet. Id. Moreover, Dr. Maher has acknowledged that platelet serotonin levels from his study cannot be used to demonstrate that plasma serotonin levels increase in those who ingest phentermine. (Joint Ex. 2B at Tab 5 at 160.)
Dr. Maher also refers to the drug Aminorex (an anorexic drug as is phentermine) as having the pharmacokinetics of inhibiting both MAO and serotonin uptake. To the extent that Dr. Maher relies on this as a basis for his opinion that phentermine synergistically interacts with fenfluramine to inhibit MAO, the court finds that such a conclusion does not reliably follow. See Joiner, 522 U.S. at 145-46 (upholding district court's decision, in case involving PCB-exposure, not to rely on study involving similar harms caused by mineral oil where no mention of PCBs were made in study).
b. Interference with Pulmonary Clearance of Serotonin.
Drs. Maher and Wellman also opine that phentermine interferes with the pulmonary clearance of serotonin in the lung. (Tr. 3/7/00 at 246-47.) However, Dr. Wellman testified that he was unaware of any scientific evidence that phentermine alone interferes with the ability of the human lung to clear serotonin. (Tr. 3/7/00 at 246-47.) Dr. Wellman also testified that he was unaware of any scientific evidence that phentermine when used with fenfluramine interfered with the pulmonary clearance of serotonin. (Tr. 3/7/00 at 247.)
Dr. Gershon agreed with this concession. (Tr. 3/8/00 at 14.)
Dr. Gershon also agreed with this concession. (Tr. 3/8/00 at 14.)
Drs. Maher and Wellman rely on the Morita and Mehendale study in support of their opinion that phentermine inhibits pulmonary clearance of serotonin. (Joint Lit. Ex. 138.) In that study, different dosages of chlorophentermine and phentermine were injected directly into the lungs of rats through the jugular vein. (Tr. 3/8/00 at 70-71 76-77.) This experiment is not comparable to the human oral ingestion of phentermine. (Tr. 3/8/00 at 75-76.) As Dr. Mehendale testified, medication taken orally is absorbed into the blood circulation and metabolized. Some of the medication is excreted and what remains would be available for absorption into the body. (Tr. 3/8/00 at 76.) Only a fraction of that remaining phentermine would be taken up by organs and tissues. (Tr. 3/8/00 at 76.)
The objective of the experiment was to investigate the effects of different doses of chlorophentermine and phentermine on lung clearance of serotonin in rats.
In addition, only the highest dose of phentermine administered in the Morita and Mehendale study — 20 mg/kg — had any effect on pulmonary clearance of serotonin. (Tr. 3/8/00 at 72-79; Joint Lit. Ex. 138 at 749 fig.3.) The human clinical dose in the study — 0.5 mg/kg — had no effect on pulmonary clearance of serotonin. (Tr. 3/8/00 at 72-79; Joint Lit. Ex. 138 at 749 fig.3.)
Dr. Mehendale referred to this dosage as a "whopping dose." (Tr. 3/8/00 at 79.) Dr. Wellman agreed that this dosage was substantially higher than the human clinical dose. (Tr. 3/7/00 at 248-51.) Moreover, the Morita and Mehendale study concluded that pulmonary clearance of serotonin was only "marginally inhibited" by this "whopping dose" of phentermine. (Joint Lit. Ex. 138 at 749 fig.3.)
Nonetheless, Plaintiffs argue that phentermine's inhibition of the pulmonary clearance of serotonin is recognized in scientific literature. (Joint Lit. Ex. 44 (Connolly) at 588; Joint Lit. Ex. 65 (Fishman) at 159; Joint Ex. 2A (Maher) at Tab 3 Ex. 10, p. 9.) These articles, however, simply cite to the Morita and Mehendale article and do not address the problems, discussed above, associated with extrapolating these study results to reach a conclusion that phentermine inhibits pulmonary clearance of serotonin in the human lung. Dr. Connolly has acknowledged that the reference in her study to phentermine's interference with pulmonary clearance of serotonin was to an animal model and that there was no scientific data that would have permitted her to extrapolate the data from the rat study to humans. (Joint Ex. 12 (Connolly) at Tab 1, at 203 206-07.)
In addition, two of the articles, Dr. Fishman's and Dr. Maher's, have referred to the Morita and Mehendale study as performed on rabbits, although it actually involved rats. (Joint Lit. Ex. 65 (Fishman) at 159; Joint Ex. 2A (Maher) at Tab 3, Ex. 10 p. 9.)
c. Serotonin Release.
Drs. Maher and Wellman also opine that phentermine causes serotonin to be released from blood platelets. However, there is no scientific evidence that phentermine causes the release of serotonin in the human periphery — from platelets or other cells into other compartments of the blood. (Tr. 3/7/00 at 242; Tr. 3/8/00 at 14.) Nor is there scientific evidence that phentermine, when combined with fenfluramine, causes serotonin to be released in the human periphery. (Tr. 3/7/00 at 243; Tr. 3/8/00 at 14.) Dr. Wellman has referred to the Fristrom study in forming his opinion that phentermine causes serotonin to be released from blood platelets. (Joint Lit. Ex. 70.) The Fristrom study measured the effect of, among other things, phentermine on platelets extracted from rabbit blood. This study is unreliable to support an extrapolation of its results to humans. The concentration of phentermine necessary to cause serotonin release from the rabbit platelets was 100 times greater than the human clinical concentration of phentermine. (Tr. 3/7/00 at 244-46.)
d. Stimulation of Serotonin Receptors.
Drs. Maher and Wellman also opine that phentermine affects serotonin receptors on heart valve tissue causing cellular proliferation. Dr. Maher relies on the Fitzgerald study for this opinion. (Joint Lit. Ex. 68.) The Fitzgerald study, according to Dr. Maher, found that "serotonin receptors on heart valve tissue, when stimulated produced the fibroplasia seen in fen-phen induced" VHD. (Joint Ex. 2A (Maher) at Tab 3 ¶ 14.) However, the Fitzgerald study expressly finds that "[p]hentermine, the other component of the `fen-phen' combination, was found to be inactive at these receptors." (Joint Lit. Ex. 68 at 79; Tr. 3/7/00 at 134-37.)
Dr. Gershon confirmed that in the Fitzgerald study, phentermine did not have an effect upon the serotonin receptors. (Tr. 3/8/00 at 19-22.)
4. Synergistic Toxicity
The Phentermine Defendants assert that synergy is a pharmacological phenomenon where the combined effect of two substances is greater than the sum of the effect of each substance alone. There is a generally accepted methodology for demonstrating synergy that involves the comparison of dose response curves of each drug alone with dose response curves for the two drugs together, using various fixed ratios of the drugs and an isobolographic analysis. There is no study in humans or animals in which synergy of the fen-phen combination has been demonstrated. (Tr. 3/8/00 at 109-110.)
Plaintiffs respond that:
the word "synergism" has both a broad and a narrow meaning. In the broadest sense, it refers to any drugdrug interaction that increases or decreases an effect of another drug. More precisely used, it means only a narrow subset of such interactions, where both drugs have an effect, say, of 1, but 1 + 1 = 3 or more. Where 1 + 1 = 2 in a measured effect, that is additivity. Sometimes, one drug has no effect, the other a mild one, but 1 + 0 = 2 or more, and then pharmacologists say there is potentiation by the drug with the zero effect. But "synergisms" in the title of Maher and Wellman's paper was used in the broad sense, including all types of these drug-drug interactions.
(Pls.' Post-Hr'g Mem. in Resp. to Defs.' Mots. to Exclude Expert Test. of Paul J. Wellman, Ph.D. and Timothy J. Maher, Ph.D. at 17-18.) Plaintiffs argue that "since it is not clear that phentermine alone can cause PPH, it is not knowable whether phentermine's boosting effect on fenfluramine PH is merely additive, or truly `synergistic.'" Id. at 17.
This argument demonstrates the unreliability of Dr. Maher's and Dr. Wellman's opinions. Based on Plaintiffs' arguments, Drs. Maher and Wellman could present each of these theories of drugdrug interaction and have the jury choose between and among them and the weight to apply to them. Because these theories have merely been posited by Drs. Maher and Wellman and not tested, allowing such testimony would not assist the trier of fact.
Plaintiffs' position on synergistic toxicity also appears to be based, at least in part, upon the notion that synergy as to one outcome (appetite suppression) establishes synergy with respect to other outcomes, namely PPH and VHD. Plaintiffs cite to a number of studies in support of their synergy claims. These studies do not support the opinions of Drs. Maher and Wellman regarding synergistic toxicity. The Weintraub Study did not examine the effects of the fen-phen combination with regard to PPH or VHD. (Joint Lit. Ex. 197.) Other studies reporting that fenfluramine and phentermine yield a larger increase in brain serotonin on the brains of rats and mice than either drug alone are also unreliable to support that notion that diet drugs can cause PPH or VHD in humans. These animal brain studies suffer from several deficiencies. First, in most of these studies, an isobolographic analysis was not employed in analyzing synergy. Second, the study improperly relies on results measuring brain serotonin and extrapolates those results to serotonin in the periphery. Third, extrapolating the data on rats to humans is unreliable for a number of reasons, including: (1) differences in species; (2) higher dosages are used in animals; (3) animals are often administered the drugs through injection rather than oral ingestion, thereby increasing the concentration of the dose; and (4) the pharmacokinetics of animals and humans differ. (Tr. 3/8/00 at 112-15.)
The Weintraub study primarily examined the effect of diet drugs with respect to weight loss and adverse side effects. The study suggested a synergistic effect of the fen-phen combination with regard to a subjective assessment of "total fullness" by study participants. (Joint Lit. Ex. 197 at 1145.) The study also reported that those on combination therapy lost the same amount of weight as those on monotherapy. (Joint Lit. Ex. 197; Joint Ex. 7 (Vorhees) at Tab 4 ¶ 14.) In addition, with regard to adverse effects, the Weintraub study found that there "was no significant difference between [the fen-phen] combination and placebo or between the three active treatments in total complaints." (Joint Lit. Ex. 197, at 1146.)
Although an isobolographic analysis was employed in the Roth and Rowland Study, the data from that study could not be properly interpreted because, among other things, the researchers used recycled rats in the study. (Joint Lit. Ex. 159; Joint Ex. 7 (Vorhees) at Tab 3 at 30-31.) In addition, the Roth and Rowland Study did not measure any relation between the diet drugs and PPH or VHD. Moreover, these authors were unable to replicate their findings in a subsequent study. (Joint Lit. Ex. 168.)
Such an extrapolation is unreliable for several reasons, including: (1) serotonin in the brain originates in the brain and does not pass out of the brain into the periphery, and serotonin in the periphery does not enter the brain (the "blood-brain barrier"); (2) serotonin in the brain is confined to highly localized synapses, while serotonin released in the periphery may circulate throughout the body in the plasma; (3) serotonin receptors in the brain and periphery differ; and (4) mechanisms for the clearance of serotonin in the brain and periphery differ. (Tr. 3/8/00 at 112-15.)
Additionally, Plaintiffs cite the Reeve study for the proposition that phentermine causes pulmonary artery vasoconstriction. (Joint Lit. Ex. 148.) The Reeve study examined the effects of phentermine and dexfenfluramine on pulmonary artery pressures in perfused rat lungs. It also examined the drugs' effects on potassium channel current and a corresponding electrical function in isolated smooth muscle cells from rats. The Reeve study does not provide reliable support to show that phentermine acts synergistically with dexfenfluramine to block potassium channels in pulmonary smooth muscle cells, or causes pulmonary artery vasoconstriction in humans. (Tr. 3/8/00 at 175-80.) Significantly, the concentration of Phentermine used was at least 100 times greater than the clinically relevant concentration in humans. (Tr. 3/8/00 at 177.)
Ion channels regulate the contraction of smooth muscle cells. (Tr. 3/8/00 at 174.)
Smooth muscle cells line all the hollow organs of the body. Specifically, they make up the wall of the pulmonary arteries. (Tr. 3/8/00 at 173.)
5. Summary
The court finds that the opinions of Drs. Maher and Wellman do not amount to scientific knowledge and that although their opinions may or may not be proven in the future, their current testimony is "based more on personal opinion than on [reliable] scientific knowledge." Allison v. McGhan Medical Corp., 184 F.3d 1300, 1319 (11th Cir. 1999). The opinions of Drs. Maher and Wellman are not generally accepted within the scientific community. Although their views have been published in a peer reviewed journal, the court notes that Drs. Maher and Wellman have not relied on any epidemiological studies, nor have they relied on any testing performed on live, whole animals.
The lack of these types of studies is not, in and of itself, fatal to Plaintiffs' proffer of these witnesses. See Heller, 167 F.3d at 158-59 (stating that district court erred to extent that it required doctor's testimony to be backed by scientific studies, but that court could consider that doctor relied on few, if any, studies linking exposure to hazardous substances) (emphasis added).
Drs. Maher and Wellman have not demonstrated reliable data to support their hypothesis that elevated levels of plasma serotonin cause PPH or VHD. With regard to Dr. Maher's and Dr. Wellman's plasma serotonin hypothesis, there is also a problem with testability. Plasma serotonin levels are difficult to measure. (Joint Ex. 5 (Gershon) at Tab 3, at 71.) Moreover, while Dr. Maher's own human study showed elevated platelet serotonin levels, there is no reliable support to extrapolate these results to plasma serotonin.
Instead, Drs. Maher and Wellman have based their opinions on what they believe would be the likely effects of phentermine, when used in combination with fenfluramine, on human serotonin mechanisms. However, these opinions are based on in vitro animal studies. To the extent that Drs. Maher and Wellman have relied on in vitro studies performed on animals, the results cannot be reliably extrapolated to an opinion on human causation. See In re Paoli R.R. Yard PCB Litig., 35 F.3d at 743 (stating that "in order for animal studies to be admissible to prove causation in humans, there must be good grounds to extrapolate from animals to humans just as the methodology of the studies must constitute good grounds to reach conclusions about the animals themselves"). Animal and human systems differ. Additionally, the concentration of phentermine used in these in vitro animal studies greatly exceeded any the human clinical dosage. These gaps in scientific data are amplified by the fact that Drs. Maher and Wellman are neither medical doctors, nor experts in epidemiology, cardiology or pulmonology.
The conclusions reached by Drs. Maher and Wellman have to "fit" with the data and the methodology that precede them. See Heller, 167 F.3d at 159. Even if their data (e.g., in vitro animal studies) and the methodology (serotonergic mechanisms) are reliable, the conclusions that Drs. Maher and Wellman have reached (that the fen-phen combination induces greater cardiovascular toxicity than does fenfluramine alone) do not reliably flow from this data and methodology. See id. Under these circumstances, the court finds that there is "too great an analytical gap" between the available scientific data and the opinions proffered by Drs. Maher and Wellman. Joiner, 522 U.S. at 146. Thus, thus the court will grant Defendants' motions to exclude the opinions of Drs. Maher and Wellman regarding the notion that the fen-phen combination induces greater cardiovascular toxicity than does fenfluramine alone.
C. Opinions Regarding Antagonistic Tolerability, Synergistic Efficacy and Increase in the Use of Pondimin.
Drs. Maher and Wellman were identified by Plaintiffs pursuant to Pretrial Order No. 417 as "experts who would testify on general causation, i.e. the ability or tendency of the drugs to cause any of the injuries alleged." PTO No. 417. At the Daubert hearing, Drs. Maher and Wellman opined that phentermine, when taken in combination with fenfluramine, reduced the unpleasant side effects of fenfluramine. Plaintiffs refer to this interaction as antagonistic tolerability. Drs. Maher and Wellman also opined that when phentermine and fenfluramine were combined, patients could take a lower dose and still lose as much weight. Plaintiffs refer to this interaction as synergistic efficacy. Drs. Maher and Wellman also opined that the pharmacological properties of phentermine caused a dramatic increase in the use of Pondimin in the United States and, thus, led to the vast majority of Pondimin-induced VHD and PPH. These opinions are quite apart from any opinion that phentermine contributes to the medical causation of PPH or VHD.
Drs. Maher and Wellman also provided the opinion that Pondimin monotherapy had minimal clinical usage because levofenfluramine caused unpleasant side effects and monotherapy required higher doses of the drug. Neither AHP nor the Phentermine Defendants have fashioned a direct challenge to these opinions. Thus, to the extent that a trial court finds them relevant, the court will not exclude these opinions on the present Daubert challenge.
1. Antagonistic Tolerability and Synergistic Efficacy.
According to Drs. Maher and Wellman, the adverse side effects of fenfluramine are caused by levofenfluramine's inhibition of the neurotransmitter dopamine. Drs. Maher and Wellman also opine that phentermine increases dopamine levels in the brain, thereby blunting the adverse effects of levofenfluramine. The Phentermine Defendants argue that Plaintiffs have not pointed to any scientific evidence concerning the effects of levofenfluramine and phentermine on dopamine in the brain. In fact, the Phentermine Defendants point out that Dr. Maher's and Dr. Wellman's paper refers to "antagonistic tolerability" as only a theoretical effect.
According to the Maher and Wellman paper, "[m]ixing phentermine with racemic fenfluramine would theoretically cancel out these dopaminergic effects, so as to minimize patient complaints and improve compliance." (Joint Lit. Ex. 203 at 724.)
Inasmuch as Plaintiffs also rely on the Weintraub and Brauer studies for their opinions regarding antagonistic tolerability, the Phentermine Defendants argue that these studies are unreliable to support the proposition. (Joint Lit. Exs. 197 28.) Drs. Maher and Wellman reported that the Weintraub study concluded that "fewer adverse effects were reported for the combination of fen-phen than for either drug alone." (Joint Lit. Ex. 203 at 723.) The Weintraub study, however, reported that there "was no significant difference between [the fen-phen] combination and placebo or between the three active treatments in total complaints." (Joint Lit. Ex. 197 at 1146.) With regard to the Brauer study, although it suggested "that phentermine may dampen some aversive effects of fenfluramine," the authors noted several limitations to their study and pointed out that their observations could only be confirmed with dose-response studies. (Joint Lit. Ex. 28 at 237-39.)
Drs. Maher and Wellman also rely on the Weintraub study for their opinion that the fen-phen combination is more effective at weight loss than the drugs alone. However, the Phentermine Defendants argue that the Weintraub study only suggested a synergistic effect of the fen-phen combination with regard to a subjective assessment of "total fullness" by study participants. (Joint Lit. Ex. 197 at 1145.) In fact, the study reported that those on combination therapy lost the same amount of weight as those on monotherapy. (Joint Lit. Ex. 197; Joint Ex. 7 (Vorhees) at Tab 4 ¶ 14.)
With regard to the Daubert issues concerning these opinions concerning antagonistic tolerability and synergistic efficacy, the court notes that Drs. Maher and Wellman are qualified to give a pharmacological explanation for the fen-phen combination. In addition, the court finds that the conclusions of Drs. Maher and Wellman could reliably follow from the studies and methodologies on which they rely. Although experts may disagree about interpretations of these studies, that goes more to the weight of the evidence than to reliability for Daubert purposes.
See supra at section I, ¶¶ 4, 4.1 and 4.2.
2. Increased Use of Pondimin
Drs. Maher and Wellman rely on several of Defendants' internal sales and marketing data for their opinion that the pharmacological properties of Phentermine caused a dramatic increase in the use of Pondimin. Neither Dr. Maher, a pharmacologist, nor Dr. Wellman, a behavioral psychologist, are qualified to testify about the sales and marketing trends involving phentermine and fenfluramine. It may be, for example, that Dr. Maher is qualified to opine on the pharmacological properties of phentermine, and Plaintiffs may seek to introduce evidence showing that phentermine, when combined with fenfluramine, caused an increase in Pondimin use. Such evidence, if admitted by the transferor court at trial, could be used to support Plaintiffs' legal argument that the Phentermine Defendants are responsible, in part, for the dangers caused by fenfluramine. However, the court finds that Drs. Maher and Wellman are not qualified to opine about the marketplace effect that phentermine had on Pondimin sales in the United States.
D. Opinions That Fenfluramines Cause PPH and VHD.
As part of their opinions, Drs. Maher and Wellman have stated that fenfluramines cause PPH and VHD. As discussed above, Drs. Maher and Wellman are not medical doctors and have limited experience in examining disease causation in humans. In fact, Drs. Maher and Wellman rely substantially on epidemiological studies to support their opinions with regard to the fenfluramines. See Pls.' Post-Hr'g Mem. in Resp. to Defs.' Mots. to Exclude Expert Test. of Paul J. Wellman, Ph.D. and Timothy J. Maher, Ph.D. at 2-3 (referring to two epidemiological studies and world-wide consensus statement that fenfluramines cause PPH). However, Drs. Maher and Wellman are not epidemiologists. In addition, to the limited extent that Drs. Maher and Wellman have done research with respect to diet drugs, it has focused mainly on phentermine and its potential synergistic effects. With this background, the court finds that Drs. Maher and Wellman are not qualified to testify about whether fenfluramine or dexfenfluramine alone cause PPH or VHD.
Indeed, the court has reviewed the opinions of Drs. Maher and Wellman with regard to phentermine's potential synergistic qualities and will exclude any testimony by these witnesses on the issue.
E. Plaintiffs' Motion to Update Record.
On May 12, 2000, Plaintiffs filed a motion to update the record. Plaintiffs seeks to admit six new exhibits relevant to Defendants' motions to exclude the testimony of Drs. Maher and Wellman: (1) Exhibit 43, Julius M. Gardin, M.D., et al., Valvular Abnormalities and Cardiovascular Status Following Exposure to Dexfenfluramine or Phentermine/Fenfluramine, 283 JAMA, No. 13 at 1703-09 (April 5, 2000); (2) Exhibit 44, Margaret R. MacLean, Pulmonary Hypertension, Anorexigens and 5-HT: Pharmacological Synergism in Action?, 20 Trends in Pharm. Sciences 490-95 (December 1999); (3) Exhibit 45, P. Valodia and J.A. Syce, The Effect of Fenfluramine on the Pulmonary Disposition of 5-Hydroxytryptamine in the Isolated Perfused Rat Lung: a Comparison with Chlorophentermine, 52 J. Pharm. Pharmacol. 53-58 (2000); (4) Exhibit 46, European Withdrawal of Anorectic Agents/Appetite Suppressants (forthcoming April 2000) 26 Current Problems in Pharmacovigilance; (5) Exhibit 47, The European Union Bans Phentermine, 4 Obesity Meds and Research News, Issue 4, at 4 (April 2000); and (6) Exhibit 48, Ismail H. Ulus, et al., Characterization of Phentermine and Related Compounds as Monoamine Oxidase (MAO) Inhibitors, 59 Biochemical Pharmacology 1611-21 (2000).
The Gardin Study (Ex. 43) was first presented in November 1998 at the annual meeting of the American Heart Association. For this hearing, the parties jointly submitted a slide containing the data on mitral valve regurgitation to which this study refers. A manuscript of the MacLean Study (Ex. 44) was marked as Exhibit 27 to Dr. Wellman's MDL deposition. It was not offered at the March 7-8, 2000 hearing. The Valodia Study (Ex. 45) does not involve or make any conclusions about phentermine. Exhibits 46 and 47 are news articles and do not qualify as "scientific" evidence. The manuscript of the Ulus Study (Ex. 48) was examined at Dr. Maher's MDL deposition and at the March 7-8, 2000 hearing.
Accordingly, the court finds that these exhibits are not new, and in some cases, not relevant. In any event, they do not present sufficient justification for the court to reopen the record. Thus, the court will deny Plaintiffs motion to update the record.
IV. CONCLUSION
For the foregoing reasons, the court will grant in part and deny in part the Phentermine Defendants' and American Home Products Corporation's motions to exclude the expert testimony of plaintiffs' experts Paul Wellman, Ph.D. and Timothy Maher, Ph.D. pursuant to Federal Rules of Evidence 702 and 703 and will deny Plaintiffs' motion to reopen the record.
An appropriate Pretrial Order follows.
PRETRIAL ORDER NO.
AND NOW, TO WIT, this day of June, 2000, upon consideration of the Phentermine Defendants' and American Home Products Corporation's motions to exclude the expert testimony of plaintiffs' experts Paul Wellman, Ph.D. and Timothy Maher, Ph.D. pursuant to Federal Rules of Evidence 702 and 703 and Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993), the responses thereto and the evidence elicited at a hearing held March 7 and 8, 2000, IT IS ORDERED that said motions are GRANTED IN PART and DENIED IN PART:
1. to the extent that Drs. Maher or Wellman seek to offer opinions that the Fen-Phen combination induces greater cardiovascular toxicity than does fenfluramine alone, the motions are GRANTED;
2. to the extent that Drs. Maher or Wellman seek to offer opinions that the fenfluramines cause primary pulmonary hypertension ("PPH") or valvular heart disease ("VHD"), the motions are GRANTED;
3. to the extent that Drs. Maher or Wellman seek to offer opinions that the pharmacology of phentermine caused a dramatic increase in the use of Pondimin in the United States, the motions are GRANTED;
4. to the extent that Drs. Maher or Wellman seek to offer opinions that Pondimin monotherapy had minimal clinical usage because levofenfluramine caused unpleasant side effects and clinical efficacy required higher doses, the motions are DENIED; and
5. to the extent that Drs. Maher or Wellman seek to offer opinions that the clinical combination of Fen-Phen caused phentermine to boost the efficacy of dexfenfluramine and blunt the unpleasant side effects of levofenfluramine in Pondimin, the motions are DENIED.
IT IS FURTHER ORDERED that Plaintiffs' Motion to UpdateDaubert Record is DENIED.